Fluoro-substituted 2-aryl-3,5-dicyano-4-indazolyl-6-methyl-1,4-dihydropyridines and uses thereof

ABSTRACT

The present invention relates to novel, fluoro-substituted 2-aryl-3,5-dicyano-4-(1H-indazol-5-yl)-6-methyl-1,4-dihydropyridine derivatives having protein tyrosine kinase inhibitory activity, to a process for the manufacture thereof and to the use thereof for the treatment of c-Met-mediated diseases or c-Met-mediated conditions, particularly Cancer and other proliferative disorders.

The present invention relates to novel, fluoro-substituted2-aryl-3,5-dicyano-4-(1H-indazol-5-yl)-6-methyl-1,4-dihydropyridinederivatives having protein tyrosine kinase inhibitory activity, to aprocess for the manufacture thereof and to the use thereof for thetreatment of c-Met-mediated diseases or c-Met-mediated conditions,particularly cancer and other proliferative disorders.

Cancer is one of the most common widespread diseases. Over 4.4 millionpeople worldwide were diagnosed with breast, colon, ovarian, lung orprostate cancer in 2002, and over 2.5 million people died of thesedevastating diseases (Globocan 2002 Report,http://www-depiarc.fr/globocan/downloads.htm). In the United Statesalone, over 1.25 million new cases and over 500 000 deaths from cancerwere predicted in 2005. The majority of these new cases were expected tobe cancers of the colon (˜100 000), lung (˜170 000), breast (˜210 000)and prostate (˜230 000). Both the incidence and prevalence of cancer ispredicted to increase by approximately 15% over the next ten years,reflecting an average growth rate of 1.4% (American Cancer Society,Cancer Facts and Figures 2005;http://www.cancer.org/docroot/STT/content/STT_(—)1x_Cancer_Facts_Figures_(—)2007.asp).

There are many ways how cancers can arise, which is one of the reasonswhy their therapy is difficult. One way is the transformation of cellsby oncoproteins, which arise from normal cellular proteins by geneticmutations, which results in a non-physiological activation of theseproteins. One family of proteins from which a number of oncoproteinsderive are tyrosine kinases (e.g. src kinase) and in particular receptortyrosine kinases (RTKs). In the past two decades, numerous avenues ofresearch have demonstrated the importance of receptor tyrosine kinase(RTK)-mediated signalling in the regulation of mammalian cell growth.Recently, results have been achieved in the clinic with selectivesmall-molecule inhibitors of tyrosine kinases as anti-tumourigenicagents.

The c-Met receptor also is a receptor tyrosine kinase. Its oncogenicpotential was identified in the early 1980s, when a mutated Met wasisolated from a chemically induced human osteosarcoma cell line whichcontained the kinase domain of the Met gene fused to a dimerizationdomain at its N-terminus [C. S. Cooper et al., Nature 311: 29-33(1984)].

The cellular Met protein is a heterodimeric transmembrane proteinsynthesized as a single chain 190 kd precursor [G. A. Rodrigues et al.,Mol. Cell. Biol. 11: 2962-70 (1991)]. The precursor is cleavedintracellularly after amino acid residue 307 to form the 50 kd α-chainand the 145 kd β-chain, which are connected by disulfide bridges. Theα-chain is entirely extracellular, whereas the β-chain spans the plasmamembrane. The β-chain is composed of an N-terminal sema domain, whichtogether with the α-chain mediates ligand binding. The remainder of theectodomain of the β-chain is composed of a cysteine-rich domain and fourimmunoglobulin domains and is followed by the transmembrane region andthe intracellular domain. The intracellular domain contains ajuxtamembrane domain, the kinase domain and a C-terminal domain, whichmediates the downstream signalling. Upon ligand binding, a dimerizationof the receptor is induced, and the kinase domain is activated by acascade of tyrosine autophosphorylation steps in the juxtamembraneregion (Y1003), the activation loop of the kinase (Y1234 and Y1235) andthe carboxy-terminal domain (Y1349 and Y1356). Phosphorylated Y1349 andY1356 comprise the multi-substrate docking site for binding adapterproteins necessary for downstream c-Met signalling [C. Ponzetto et al.,Cell 77: 261-71 (1994)]. One of the most crucial substrates for c-Metsignalling is the scaffolding adaptor protein Gab1, which binds toeither Y1349 or Y1356 via an unusual phosphotyrosine binding site(termed mbs: met binding site) which causes a unique prolongedintracellular signal. Another important substrate is the adaptor proteinGrb2. Depending on the cellular context, these adaptors mediate theactivation of various intracellular signal pathways like the onessignalling via ERK/MAPK, PI3K/Akt, Ras, JNK, STAT, NFκB and β-catenin.

c-Met is uniquely activated by hepatocyte growth factor (HGF), alsoknown as scatter factor, and its splice variants, which is its onlyknown biologically active ligand [L. Naldini et al., Oncogene 6: 501-4(1991)]. HGF has a distinct structure which reveals similarities toproteinases of the plasminogen family. It is composed of anamino-terminal domain followed by four kringle domains and a serineprotease homology domain, which is not enzymatically active. Similar toc-Met, HGF is synthesized as an inactive single chain precursor(pro-HGF), which is extracellularly cleaved by serine proteases (e.g.plasminogen activators and coagulation factors) and converted into adisulfide-linked active α- and β-chain heterodimer. HGF binds heparansulfate proteoglycans with high affinity, which keeps it mainlyassociated with the extracellular matrix and limits its diffusion.Crystal structure analyses indicate that HGF forms a dimer, which uponbinding to c-Met induces dimerization of the receptor.

HGF is expressed by mesenchymal cells, and its binding to c-Met, whichis widely expressed in particular in epithelial cells, results inpleiotropic effects in a variety of tissues including epithelial,endothelial, neuronal and hematopoetic cells. The effects generallyinclude one or all of the following phenomena: i) stimulation ofmitogenesis; HGF was identified by its mitogenic activity onhepatocytes; ii) stimulation of invasion and migration; in anindependent experimental approach, HGF was identified as scatter factorbased on its induction of cell motility (“scattering”); and iii)stimulation of morphogenesis (tubulogenesis). HGF induces the formationof branched tubules from canine kidney cells in a collagen matrix.Furthermore, evidence from genetically modified mice and from cellculture experiments indicate that c-Met acts as a survival receptor andprotects cells from apoptosis [N. Tomita et al., Circulation 107:1411-1417 (2003); S. Ding et al., Blood 101: 4816-4822 (2003); Q. Zenget al., J. Biol. Chem. 277: 25203-25208 (2002); N. Horiguchi et al.,Oncogene 21: 1791-1799 (2002); A. Bardelli et al., Embo J. 15: 6205-6212(1996); P. Longati et al., Cell Death Differ. 3: 23-28 (1996); E. M.Rosen, Symp. Soc. Exp. Biol. 47: 227-234 (1993)]. The coordinatedexecution of these biological processes by HGF results in a specificgenetic program which is termed as “invasive growth”.

Under normal conditions, c-Met and HGF are essential for embryonicdevelopment in mice, in particular for the development of the placentaand the liver and for the directional migration of myoblasts from thesomites of the limbs. Genetic disruption of the c-Met or HGF genesresults in identical phenotypes which shows their unique interaction.The physiological role of c-Met/HGF in the adult organism is less wellunderstood, but experimental evidence suggests that they are involved inwound healing, tissue regeneration, hemopoiesis and tissue homeostasis.

The identification of the oncoprotein TPR-MET was a first hint thatc-Met may play a role in tumourigenesis. Additional substantial evidenceis derived from a number of different experimental approaches.Overexpression of c-Met or HGF in human and murine cell lines inducestumourigenicity and a metastatic phenotype when expressed in nude mice.Transgenic overexpression of c-Met or HGF induces tumourigenesis inmice.

Most intriguingly, missense mutations of c-Met or mutations whichactivate the receptor have been identified in sporadic and hereditarypapillary kidney carcinomas (HPRC) as well as in other cancer types likelung, gastric, liver, head and neck, ovarian and brain cancers.Significantly, specific c-Met mutations in HPRC families segregate withdisease, forming a causal link between c-Met activation and human cancer[L. Schmidt et al., Nat. Genet. 16: 68-73 (1997); B. Zbar et al., Adv.Cancer Res. 75: 163-201 (1998)]. Activation mutations with the strongesttransforming activities are located in the activation loop (D1228N/H andY1230H/D/C) and in the adjacent P+1 loop (M1250T). Additional weakermutations have been found near the catalytic loop and within the A lobeof the kinase domain. Furthermore, some mutations in the juxtamembranedomain of c-Met have been observed in lung tumours which do not directlyactivate the kinase, but rather stabilize the protein by rendering itresistant to ubiquitination and subsequent degradation [M. Kong-Beltranet al., Cancer Res. 66: 283-9 (2006); T. E. Taher et al., J. Immunol.169: 3793-800 (2002); P. Peschard et al., Mol. Cell. 8: 995-1004(2001)]. Interestingly, somatic mutations of c-Met are associated withincreased aggressiveness and extensive metastases in various cancers.While the frequency of germ line and somatic mutations is low (below5%), other major mechanisms have been observed leading to a deregulationof the c-Met signalling, in the absence of mutations, by paracrine orautocrine mechanisms. Paracrine activation has been observed in tumourswhich are derived from mesenchymal cells, like osteosarcomas orrhabdomyosarcomas, which physiologically produce HGF, and inglioblastomas and mamma carcinomas which are of ectodermal origin.

However, the most frequent cases are carcinomas where c-Met isoverexpressed as observed in carcinomas of the colon, pancreas, stomach,breast, prostate, ovary and liver. Overexpression may arise, forexample, by gene amplification as observed in gastric and lung tumourcell lines. Very recently, overexpression of c-Met was detected in lungtumour cell lines which acquired resistance to EGF receptor inhibition[J. A. Engelmann et al., Science 316: 1039-1043 (2007)]. Some epithelialtumours that overexpress c-Met also co-express HGF, resulting in anautocrine c-Met/HGF stimulatory loop and thereby circumventing the needfor stromal cell-derived HGF.

In general, it has been found that aberrant activation of c-Met in humancancer is typically associated with a poor prognosis, regardless of thespecific mechanism [J. G. Christensen et al., Cancer Lett. 225: 1-26(2005)].

In summary, a great number of in vitro and in vivo studies have beenperformed that validate c-Met as an important cancer target, and acomprehensive list can be viewed at http://www.vai.org/met [C.Birchmeier et al., Nat. Rev. Mol. Cell. Biol. 4: 915-25 (2003)]. Severalstrategies have been followed to attenuate aberrant Met signalling inhuman tumours including HGF antagonists and small molecule inhibitors,amongst others. A number of small molecule inhibitors are currently inclinical development, such as ARQ-197 (Arqule), foretinib (XL-880,Exelixis/GSK), and PH-2341066 (Pfizer); they have recently been reviewed[J. J. Cui, Expert Opin. Ther. Patents 17: 1035-45 (2007)].

In WO 2006/066011-A2, haloalkyl-substituted 3-cyano-1,4-dihydropyridinederivatives with an aryl or heteroaryl group in 4-position have beendescribed as modulators both of steroidal receptors and calcium channelactivities thus being especially useful for the treatment ofcardiovascular diseases. A method for the treatment of Alzheimer'sdisease using 4-phenyl-1,4-dihydropyridine derivatives has been claimedin WO 2006/074419-A2.

Variously substituted 3-cyano-4-heteroaryl-1,4-dihydropyridinespossessing c-Met kinase inhibitory activity have recently been disclosedin WO 2008/071451-A1. During further investigation of this novelstructural class of c-Met inhibitors it emerged, however, that candidatecompounds were frequently compromised by an unsatisfactory oralbioavailability which turned out to be significantly lower thaninitially expected from blood clearance determinations in rats. As oralbioavailability also depends on how well a compound is absorbed, andgiven the pharmacokinetic and physico-chemical profile of thesecompounds, it was hypothesized that low solubility and/or inadequatepermeability across the gastro-intestinal tract might lead to suchlimitations in the absorption.

The technical problem to be solved according to the present inventionmay therefore be seen in identifying alternative compounds with potentinhibitory activity on the c-Met kinase which would reveal an increasein solubility and/or permeability, subsequently leading to an increaseof the fraction absorbed after peroral administration of thesecompounds.

Surprisingly, it has now been found that2-aryl-3,5-dicyano-4-(1H-indazol-5-yl)-6-methyl-1,4-dihydropyridinederivatives having a difluoro- or trifluoro-substitution at the methylgroup in 6-position exhibit significantly improved permeabilityproperties in vitro as assessed in a well-established intestinal cellassay.

Thus, in one aspect, the present invention relates to fluoro-substituted2-aryl-3,5-dicyano-4-(1H-indazol-5-yl)-6-methyl-1,4-dihydropyridinederivatives of the general formula (I)

-   wherein-   Ar is phenyl or 5- or 6-membered heteroaryl each of which may be    substituted with one or two substituents independently selected from    the group consisting of fluoro, chloro, bromo, cyano, nitro,    (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, amino and mono-(C₁-C₄)-alkylamino,    -   wherein said (C₁-C₄)-alkyl and (C₁-C₄)-alkoxy substituents may        be further substituted with up to three fluoro atoms,-   R¹ is hydrogen or fluoro,-   R² is hydrogen or methyl,-   R³ is hydrogen or fluoro,-   and-   R⁴ is hydrogen or (C₁-C₄)-alkyl.

The compounds according to this invention can also be present in theform of their salts, hydrates and/or solvates.

Salts for the purposes of the present invention are preferablypharmaceutically acceptable salts of the compounds according to theinvention (for example, see S. M. Berge et al., “Pharmaceutical Salts”,J. Pharm. Sci. 1977, 66, 1-19).

Hydrates of the compounds of the invention or their salts arestoichiometric compositions of the compounds or salts with water, suchas, for example, hemi-, mono- or dihydrates.

Solvates of the compounds of the invention or their salts arestoichiometric compositions of the compounds or salts with solvents.

The compounds of this invention may, either by nature of asymmetriccenters or by restricted rotation, be present in the form of isomers(enantiomers, diastereomers). Any isomer may be present in which theasymmetric center is in the (R), (S)-, or (R,S)-configuration.

It will also be appreciated that when two or more asymmetric centers arepresent in the compounds of the invention, several diastereomers andenantiomers of the exemplified structures will often be possible, andthat pure diastereomers and pure enantiomers represent preferredembodiments.

All isomers, whether separated, pure, partially pure, or indiastereomeric or racemic mixture, of the compounds of this inventionare encompassed within the scope of this invention. The purification ofsaid isomers and the separation of said isomeric mixtures may beaccomplished by standard techniques known in the art. For example,diastereomeric mixtures can be separated into the individual isomers bychromatographic processes or crystallization, and racemates can beseparated into the respective enantiomers either by chromatographicprocesses on chiral phases or by resolution.

In addition, all possible tautomeric forms of the compounds describedabove are included according to the present invention.

Unless otherwise stated, the following definitions apply for thesubstituents and residues used throughout this specification and claims:

Alkyl in general represents a straight-chain or branched saturatedhydrocarbon radical having 1 to 4 carbon atoms. Non-limiting examplesinclude methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl and tert-butyl. The same applies to radicals such as alkoxy,alkylamino and the like.

Alkoxy illustratively and preferably represents methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy and tert-butoxy.

Monoalkylamino in general represents an amino radical having one alkylresidue attached to the nitrogen atom. Non-limiting examples includemethylamino, ethylamino, n-propylamino, iso-propylamino, n-butylaminoand tert-butylamino.

Heteroaryl in general represents a monocyclic, aromatic heterocyclicradical having a total number of 5 or 6 ring atoms, including 3 to 5carbon atoms and up to 2 heteroatoms independently selected from thegroup consisting of N, O and S, which ring system is bonded via a ringcarbon atom. Non-limiting examples include furyl, pyrrolyl, thienyl,pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl. Preference is given to6-membered heteroaryl radicals such as pyridyl and pyrimidinyl, and to5-membered heteroaryl radicals such as thienyl, pyrazolyl, imidazolyl,oxazolyl, thiazolyl, isoxazolyl and isothiazolyl.

In a preferred embodiment, the present invention relates to compounds offormula (I), wherein

-   Ar is phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl, imidazolyl,    oxazolyl, thiazolyl, isoxazolyl or isothiazolyl each of which may be    substituted with one or two substituents independently selected from    the group consisting of fluoro, chloro, cyano, methyl,    difluoromethyl, trifluoromethyl, ethyl, methoxy, trifluoromethoxy    and ethoxy,-   R¹ is hydrogen or fluoro,-   R² is hydrogen,-   R³ is hydrogen or fluoro,-   and-   R⁴ is hydrogen, methyl or ethyl.

In a particularly preferred embodiment, the present invention relates tocompounds of formula (I), wherein

-   Ar is phenyl, pyridyl or oxazolyl each of which may be substituted    with one or two substituents independently selected from the group    consisting of fluoro, chloro, methyl, trifluoromethyl and methoxy,-   R¹ is hydrogen or fluoro,-   R² is hydrogen,-   R³ is hydrogen or fluoro,-   and-   R⁴ is methyl.

In another embodiment, the present invention relates to a process forpreparing the compounds of general formula (I), characterized in that anindazolyl aldehyde of formula (II)

wherein R³ and R⁴ have the meanings described above,is reacted either[A] with a ketonitrile of formula (III)

-   -   wherein Ar has the meaning described above,    -   in the presence of an acid, acid/base combination and/or        dehydrating agent to give a compound of formula (IV)

-   -   wherein Ar, R³ and R⁴ have the meanings described above,    -   and the latter is then condensed with an enaminonitrile of        formula (V)

-   -   wherein R¹ has the meaning described above,    -   to yield the compound of formula (I-A)

-   -   wherein Ar, R¹, R³ and R⁴ have the meanings described above,        or        [B] with a ketonitrile of formula (VI)

-   -   wherein R¹ has the meaning described above,    -   optionally in the presence of a base and/or dehydrating agent to        give a compound of formula (VII)

-   -   wherein R¹, R³ and R⁴ have the meanings described above,    -   and the latter is then condensed with an enaminonitrile of        formula (VIII)

-   -   wherein Ar has the meaning described above,    -   in the presence of an acid to also yield the compound of formula        (I-A)

-   -   wherein Ar, R¹, R³ and R⁴ have the meanings described above,        optionally followed by dihydropyridine N-methylation employing a        compound of formula (IX)

CH₃—X  (IX),

whereinX represents a leaving group such as halogen, mesylate, triflate,tosylate or sulfate, in the presence of a base to give the compound offormula (I-B)

wherein Ar, R¹, R³ and R⁴ have the meanings described above,and optionally followed, where appropriate, by (i) separating thecompounds (I-A) and (I-B) into their respective enantiomers and/ordiastereomers, preferably using chromatographic methods, and/or (ii)converting the compounds (I-A) and (I-B) into their respective hydratesor solvates by treatment with the corresponding solvents.

The process variants [A] (II)+(III)→(IV), (IV)+(V)→(I-A) and [B](II)+(VI)→(VII), (VII)+(VIII)→(I-A) may both be carried out in twoseparate steps as described above, or by using a one-pot procedure, i.e.without explicit isolation of the respective intermediate compounds (IV)and (VII). In some cases, depending on the reactivity of individualreactants, it may also be feasible for preparing the compounds offormula (I-A) to perform a one-flask/three-component condensationreaction of compounds (II), (III) and (V) [A], or (II), (VI) and (VIII)[B] [for the synthesis of 1,4-dihydropyridines in general, see, forexample, D. M. Stout, A. I. Meyers, Chem. Rev. 1982, 82, 223-243; H.Meier et al., Liebigs Ann. Chem. 1977, 1888; H. Meier et al., ibid.1977, 1895; H. Meier et al., ibid. 1976, 1762; F. Bossert et al., Angew.Chem. 1981, 93, 755].

Process steps (II)+(III)→(IV), (IV)+(V)→(I-A), (II)+(VI)→(VII) and(VII)+(VIII)→(I-A) are generally carried out in an inert solvent at atemperature ranging from +20° C. to the boiling point of the solventunder atmospheric pressure.

Solvents suitable for this purpose are, for example, alcohols such asmethanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol orn-pentanol, hydrocarbons such as hexane, cyclohexane, benzene, tolueneor xylene, halohydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, trichloroethane, 1,2-dichloroethane, chlorobenzeneor chlorotoluene, ethers such as tetrahydrofuran, 1,4-dioxane or1,2-dimethoxyethane, or other solvents such as acetonitrile or aceticacid. It is likewise possible to use mixtures of these solvents.Reactions (II)+(III)→(IV) and (II)+(VI)→(VII) are preferably performedin dichloromethane, toluene, ethanol, n-propanol, isopropanol, n-butanolor n-pentanol at the respective reflux temperature under atmosphericpressure, and reactions (IV)+(V)→(I-A) and (VII)+(VIII)→(I-A) arepreferably carried out in n-propanol, isopropanol, n-butanol,n-pentanol, xylene, acetic acid or mixtures thereof also at refluxtemperature under atmospheric pressure.

Reaction (II)+(III)→(IV) may advantageously take place in the presenceof an acid, an acid/base combination and/or a dehydrating agent such as,for example, molecular sieves. Examples of suitable acid catalysts areacetic acid, trifluoroacetic acid, methanesulfonic acid orp-toluenesulfonic acid; suitable bases are in particular piperidine orpyridine. Depending on the reactivity of the components, conversion(II)+(VI)→(VII) may be performed without further auxiliary reagents, orit can be facilitated by a customary amine base, such as piperidine,and/or a dehydrating agent, such as molecular sieves. Reactions(IV)+(V)→(I-A) and (VII)+(VIII)→(I-A) are usually carried out in thepresence of an acid; preferably, acetic acid is used both as acidcatalyst and solvent or cosolvent.

Inert solvents for the methylation reaction (I-A)+(IX)→(I-B) are, forexample, ethers such as diethyl ether, methyl tert-butyl ether,tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, hydrocarbons suchas benzene, toluene, xylene, hexane or cyclohexane, halohydrocarbonssuch as dichloromethane, trichloromethane, tetrachloromethane,1,2-dichloroethane, trichloroethane, tetrachloroethane, chlorobenzene orchlorotoluene, or other solvents such as acetonitrile,N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),N,N′-dimethylpropylene urea (DMPU), N-methylpyrrolidinone (NMP) orpyridine. It is also feasible to use mixtures of these solvents.Preferably, dichloromethane, tetrahydrofuran, N,N-dimethylformamide ormixtures thereof are employed.

Bases suitable for process step (I-A)+(IX)→(I-B) are in particularalkali metal or alkaline earth metal carbonates such as lithium, sodium,potassium, calcium or caesium carbonate, alkali metal hydrides such assodium or potassium hydride, sterically hindered alkali alkoxides suchas sodium or potassium tert-butoxide, sterically hindered alkali amidessuch as lithium, sodium or potassium bis(trimethylsilyl)amide or lithiumdiisopropylamide, or organic amines such as triethylamine,N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine orpyridine. Potassium carbonate, caesium carbonate or sodium hydride arepreferably used.

Reaction (I-A)+(IX)→(I-B) is generally performed under atmosphericpressure at a temperature range from −20° C. to +100° C., preferably at0° C. to +50° C.

The compounds of the formulae (II), (III), (V), (VI), (VIII) and (IX)are either commercially available, known from the literature, or can beprepared from readily available starting materials by adaptation ofstandard methods described in the literature (for further references,see experimental section below).

The preparation of the compounds of the invention can be illustrated bymeans of the following synthesis schemes. More detailed procedures arepresented below in the experimental section describing the Examples.

Methods of Use

The compounds of the present invention are potent inhibitors of theactivity or expression of receptor tyrosine kinases, particularly of thec-Met receptor tyrosine kinase. Moreover, the compounds of the inventionare characterized by an increased permeability in intestinal epithelialcells, facilitating the absorption of these compounds from thegastro-intestinal tract after peroral administration. Therefore, thecompounds of formula (I) are expected to be valuable as therapeuticagents.

Accordingly, in another embodiment, the present invention provides amethod of treating disorders relating to or mediated by c-Met kinaseactivity in a patient in need of such treatment, comprisingadministering to the patient an effective amount of a compound offormula (I) as defined above. In certain embodiments, the disordersrelating to c-Met kinase activity are cell proliferative disorders,particularly cancer.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of a disease or disorder, such as a carcinoma.

The term “subject” or “patient” includes organisms which are capable ofsuffering from a cell proliferative disorder or who could otherwisebenefit from the administration of a compound of the invention, such ashuman and non-human animals. Preferred humans include human patientssuffering from or prone to suffering from a cell proliferative disorderor associated state, as described herein. The term “non-human animals”includes vertebrates, e.g., mammals, such as non-human primates, sheep,cow, dog, cat and rodents, e.g., mice, and non-mammals, such aschickens, amphibians, reptiles, etc.

The term “disorders relating to or mediated by c-Met” shall includediseases associated with or implicating c-Met activity, for example thehyperactivity of c-Met, and conditions that accompany with thesediseases. Examples of “disorders relating to or mediated by c-Met”include disorders resulting from overstimulation of c-Met due toabnormally high amount of c-Met or mutations in c-Met, or disordersresulting from abnormally high amount of c-Met activity due toabnormally high amount of c-Met or mutations in c-Met.

The term “hyperactivity of c-Met” refers to either c-Met expression incells which normally do not express c-Met or c-Met activity by cellswhich normally do not possess active c-Met or increased c-Met expressionleading to unwanted cell proliferation or mutations leading toconstitutive activation of c-Met.

The term “cell proliferative disorder” includes disorders involving theundesired or uncontrolled proliferation of a cell. The compounds of thepresent invention can be utilized to prevent, inhibit, block, reduce,decrease, control, etc., cell proliferation and/or cell division, and/orproduce apoptosis. This method comprises administering to a subject inneed thereof, including a mammal, including a human, an amount of acompound of this invention, or a pharmaceutically acceptable salt,isomer, polymorph, metabolite, hydrate or solvate thereof which iseffective to treat or prevent the disorder.

Cell proliferative or hyper-proliferative disorders in the context ofthis invention include, but are not limited to, e.g., psoriasis, keloidsand other hyperplasias affecting the skin, skeletal disorders,angiogenic or blood vessel proliferative disorders, pulmonaryhypertension, fibrotic disorders, mesangial cell proliferativedisorders, colonic polyps, polycystic kidney disease, benign prostatehyperplasia (BPH), and solid tumors, such as cancers of the breast,respiratory tract, brain, reproductive organs, digestive tract, urinarytract, eye, liver, skin, head and neck, thyroid, parathyroid, and theirdistant metastases. Those disorders also include lymphomas, sarcomas andleukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginaland vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral, and hereditary andsporadic papillary renal cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer, and squamous cell cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma,Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

Fibrotic proliferative disorders, i.e. the abnormal formation ofextracellular matrices, that may be treated with the compounds andmethods of the present invention include lung fibrosis, atherosclerosis,restenosis, hepatic cirrhosis, and mesangial cell proliferativedisorders, including renal diseases such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, transplant rejection, and glomerulopathies.

Other conditions in humans or other mammals that may be treated byadministering a compound of the present invention include tumor growth,retinopathy, including diabetic retinopathy, ischemic retinal-veinocclusion, retinopathy of prematurity and age-related maculardegeneration, rheumatoid arthritis, psoriasis, and bullous disordersassociated with subepidermal blister formation, including bullouspemphigoid, erythema multiforme and dermatitis herpetiformis.

The compounds of the present invention may also be used to prevent andtreat diseases of the airways and the lung, diseases of thegastro-intestinal tract as well as diseases of the bladder and bileduct.

The disorders mentioned above have been well characterized in humans,but also exist with a similar etiology in other animals, includingmammals, and can be treated by administering pharmaceutical compositionsof the present invention.

Compounds of formula (I) may be administered as the sole pharmaceuticalagent or in combination with one or more additional therapeutic agentswhere the combination causes no unacceptable adverse effects. Thiscombination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of formula (I) and one ormore additional therapeutic agents, as well as administration of thecompound of formula (I) and each additional therapeutic agent in its ownseparate pharmaceutical dosage formulation. For example, a compound offormula (I) and a therapeutic agent may be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent may be administered in separate dosageformulations.

Where separate dosage formulations are used, the compound of formula (I)and one or more additional therapeutic agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

In particular, the compounds of the present invention may be used infixed or separate combination with other anti-tumor agents such asalkylating agents, anti-metabolites, plant-derived anti-tumor agents,hormonal therapy agents, topoisomerase inhibitors, camptothecinderivatives, kinase inhibitors, targeted drugs, antibodies, interferonsand/or biological response modifiers, anti-angiogenic compounds, andother anti-tumor drugs. In this regard, the following is a non-limitinglist of examples of secondary agents that may be used in combinationwith the compounds of the present invention:

-   -   Alkylating agents include, but are not limited to, nitrogen        mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa,        ranimustine, nimustine, temozolomide, altretamine, apaziquone,        brostallicin, bendamustine, carmustine, estramustine,        fotemustine, glufosfamide, mafosfamide, bendamustin, and        mitolactol; platinum-coordinated alkylating compounds include,        but are not limited to, cisplatin, carboplatin, eptaplatin,        lobaplatin, nedaplatin, oxaliplatin, and satraplatin;    -   Anti-metabolites include, but are not limited to, methotrexate,        6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone        or in combination with leucovorin, tegafur, doxifluridine,        carmofur, cytarabine, cytarabine ocfosfate, enocitabine,        gemcitabine, fludarabin, 5-azacitidine, capecitabine,        cladribine, clofarabine, decitabine, eflornithine,        ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan,        nelarabine, nolatrexed, ocfosfite, disodium premetrexed,        pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate,        vidarabine, vincristine, and vinorelbine;    -   Hormonal therapy agents include, but are not limited to,        exemestane, Lupron, anastrozole, doxercalciferol, fadrozole,        formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors,        17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone        acetate, 5-alpha reductase inhibitors such as finasteride and        epristeride, anti-estrogens such as tamoxifen citrate and        fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,        letrozole, anti-androgens such as bicalutamide, flutamide,        mifepristone, nilutamide, Casodex, and anti-progesterones and        combinations thereof;    -   Plant-derived anti-tumor substances include, e.g., those        selected from mitotic inhibitors, for example epothilones such        as sagopilone, ixabepilone and epothilone B, vinblastine,        vinflunine, docetaxel, and paclitaxel;    -   Cytotoxic topoisomerase inhibiting agents include, but are not        limited to, aclarubicin, doxorubicin, amonafide, belotecan,        camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,        diflomotecan, irinotecan, topotecan, edotecarin, epimbicin,        etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,        pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and        combinations thereof;    -   Immunologicals include interferons such as interferon alpha,        interferon alpha-2a, interferon alpha-2b, interferon beta,        interferon gamma-1a and interferon gamma-n1, and other immune        enhancing agents such as L19-IL2 and other IL2 derivatives,        filgrastim, lentinan, sizofilan, TheraCys, ubenimex,        aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,        denileukin, gemtuzumab, ozogamicin, ibritumomab, imiquimod,        lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,        sargramostim, tasonermin, tecleukin, thymalasin, tositumomab,        Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab, and        Provenge;    -   Biological response modifiers are agents that modify defense        mechanisms of living organisms or biological responses such as        survival, growth or differentiation of tissue cells to direct        them to have anti-tumor activity; such agents include, e.g.,        krestin, lentinan, sizofuran, picibanil, ProMune, and ubenimex;    -   Anti-angiogenic compounds include, but are not limited to,        acitretin, aflibercept, angiostatin, aplidine, asentar,        axitinib, bevacizumab, brivanib alaninat, cilengtide,        combretastatin, endostatin, fenretinide, halofuginone,        pazopanib, ranibizumab, rebimastat, recentin, regorafenib,        removab, revlimid, sorafenib, squalamine, sunitinib, telatinib,        thalidomide, ukrain, vatalanib, and vitaxin;    -   Antibodies include, but are not limited to, trastuzumab,        cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab,        lumiliximab, catumaxomab, atacicept, oregovomab, and        alemtuzumab;    -   VEGF inhibitors such as, e.g., sorafenib, regorafenib,        bevacizumab, sunitinib, recentin, axitinib, aflibercept,        telatinib, brivanib alaninate, vatalanib, pazopanib, and        ranibizumab;    -   EGFR (HER1) inhibitors such as, e.g., cetuximab, panitumumab,        vectibix, gefitinib, erlotinib, and Zactima;    -   HER2 inhibitors such as, e.g., lapatinib, tratuzumab, and        pertuzumab;    -   mTOR inhibitors such as, e.g., temsirolimus,        sirolimus/Rapamycin, and everolimus;    -   c-Met inhibitors;    -   PI3K and AKT inhibitors;    -   CDK inhibitors such as roscovitine and flavopiridol;    -   Spindle assembly checkpoints inhibitors and targeted        anti-mitotic agents such as PLK inhibitors, Aurora inhibitors        (e.g. Hesperadin), checkpoint kinase inhibitors, and KSP        inhibitors;    -   HDAC inhibitors such as, e.g., panobinostat, vorinostat, MS275,        belinostat, and LBH589;    -   HSP90 and HSP70 inhibitors;    -   Proteasome inhibitors such as bortezomib and carfilzomib;    -   Serine/threonine kinase inhibitors including MEK inhibitors and        Raf inhibitors such as sorafenib;    -   Farnesyl transferase inhibitors such as, e.g., tipifarnib;    -   Tyrosine kinase inhibitors including, e.g., dasatinib,        nilotibib, regorafenib, bosutinib, sorafenib, bevacizumab,        sunitinib, cediranib, axitinib, aflibercept, telatinib, imatinib        mesylate, brivanib alaninate, pazopanib, ranibizumab, vatalanib,        cetuximab, panitumumab, vectibix, gefitinib, erlotinib,        lapatinib, tratuzumab, pertuzumab, and c-Kit inhibitors;    -   Vitamin D receptor agonists;    -   Bcl-2 protein inhibitors such as obatoclax, oblimersen sodium,        and gossypol;    -   Cluster of differentiation 20 receptor antagonists such as,        e.g., rituximab;    -   Ribonucleotide reductase inhibitors such as, e.g., gemcitabine;    -   Tumor necrosis apoptosis inducing ligand receptor 1 agonists        such as, e.g., mapatumumab;    -   5-Hydroxytryptamine receptor antagonists such as, e.g., rEV598,        xaliprode, palonosetron hydrochloride, granisetron, Zindol, and        AB-1001;    -   Integrin inhibitors including alpha5-beta1 integrin inhibitors        such as, e.g., E7820, JSM 6425, volociximab, and endostatin;    -   Androgen receptor antagonists including, e.g., nandrolone        decanoate, fluoxymesterone, Android, Prost-aid, andromustine,        bicalutamide, flutamide, apo-cyproterone, apo-flutamide,        chlormadinone acetate, Androcur, Tabi, cyproterone acetate, and        nilutamide;    -   Aromatase inhibitors such as, e.g., anastrozole, letrozole,        testolactone, exemestane, aminoglutethimide, and formestane;    -   Matrix metalloproteinase inhibitors;    -   Other anti-cancer agents including, e.g., alitretinoin,        ampligen, atrasentan bexarotene, bortezomib, bosentan,        calcitriol, exisulind, fotemustine, ibandronic acid,        miltefosine, mitoxantrone, I-asparaginase, procarbazine,        dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,        tazaroten, velcade, gallium nitrate, canfosfamide, darinaparsin,        and tretinoin.

In a preferred embodiment, the compounds of the present invention may beused in combination with chemotherapy (i.e. cytotoxic agents),anti-hormones and/or targeted therapies such as other kinase inhibitors(for example, EGFR inhibitors), mTOR inhibitors and angiogenesisinhibitors.

The compounds of the present invention may also be employed in cancertreatment in conjunction with radiation therapy and/or surgicalintervention.

Furthermore, the compounds of formula (I) may be utilized, as such or incompositions, in research and diagnostics, or as analytical referencestandards, and the like, which are well known in the art.

Pharmaceutical Compositions and Methods of Treatment

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) as defined above, together with apharmaceutically acceptable carrier.

In still another aspect, the invention provides a process for preparinga pharmaceutical composition. The process includes the step ofcomprising combining at least one compound of formula (I) as definedabove with at least one pharmaceutically acceptable carrier, andbringing the resulting combination into a suitable administration form.

The active component of formula (I) can act systemically and/or locally.For this purpose, it can be applied in a suitable manner, for exampleorally, parenterally, pulmonally, nasally, sublingually, lingually,buccally, rectally, transdermally, conjunctivally, otically, or as animplant or stent.

For these application routes, the active component of formula (I) can beadministered in suitable application forms.

Useful oral application forms include application forms which releasethe active component rapidly and/or in modified form, such as, forexample, tablets (non-coated and coated tablets, for example with anenteric coating), capsules, sugar-coated tablets, granules, pellets,powders, emulsions, suspensions, solutions and aerosols.

Parenteral application can be carried out with avoidance of anabsorption step (intravenously, intraarterially, intracardially,intraspinally or intralumbarly) or with inclusion of an absorption(intramuscularly, subcutaneously, intracutaneously, percutaneously orintraperitoneally). Useful parenteral application forms includeinjection and infusion preparations in the form of solutions,suspensions, emulsions, lyophilisates and sterile powders.

Forms suitable for other application routes include, for example,inhalatory pharmaceutical forms (including powder inhalers, nebulizers),nasal drops, solutions or sprays, tablets or capsules to be administeredlingually, sublingually or buccally, suppositories, ear and eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakemixtures), lipophilic suspensions, ointments, creams, milk, pastes,dusting powders, implants or stents.

In a preferred embodiment, the pharmaceutical composition comprising acompound of formula (I) as defined above is provided in a form suitablefor oral administration. In another preferred embodiment, thepharmaceutical composition comprising a compound of formula (I) asdefined above is provided in a form suitable for intravenousadministration.

The active component of formula (I) can be converted into the recitedapplication forms in a manner known per se. This is carried out usinginert non-toxic, pharmaceutically suitable excipients. These include,inter alia, carriers (for example microcrystalline cellulose), solvents(for example liquid polyethylene glycols), emulsifiers (for examplesodium dodecyl sulphate), dispersing agents (for examplepolyvinylpyrrolidone), synthetic and natural biopolymers (for examplealbumin), stabilizers (for example antioxidants such as ascorbic acid),colorants (for example inorganic pigments such as iron oxides) or tasteand/or odor corrigents.

In another embodiment, the invention provides a method of treating acell proliferative disorder in a patient in need of such treatment,comprising administering to the patient an effective amount of acompound of formula (I) as defined above. In certain embodiments, thecell proliferative disorder is cancer.

In still another aspect, the invention provides use of a compound offormula (I) as defined above for manufacturing a pharmaceuticalcomposition for the treatment or prevention of a cell proliferativedisorder. In certain embodiments, the cell proliferative disorder iscancer.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically-acceptable carrier.

Regardless of the route of administration selected, the compounds of theinvention, which may be used in a suitable hydrated form, and/or thepharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of the invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient, composition, and mode of administration, without being toxic tothe patient. An exemplary dose range is from 0.01 to 100 mg/kg per dayor 0.1 to 150 mg/kg per day.

In certain embodiments, the compound of the invention can be used incombination therapy with conventional cancer chemotherapeutics.Conventional treatment regimens for leukemia and for other tumorsinclude radiation, drugs, or a combination of both.

Determination of a therapeutically effective anti-proliferative amountor a prophylactically effective anti-proliferative amount of thecompounds of the invention can be readily made by the physician orveterinarian (the “attending clinician”), as one skilled in the art, bythe use of known techniques and by observing results obtained underanalogous circumstances. The dosages may be varied depending upon therequirements of the patient in the judgment of the attending clinician;the severity of the condition being treated and the particular compoundbeing employed. In determining the therapeutically effectiveanti-proliferative amount or dose, and the prophylactically effectiveanti-proliferative amount or dose, a number of factors are considered bythe attending clinician, including, but not limited to: the specificcell proliferative disorder involved; pharmacodynamic characteristics ofthe particular agent and its mode and route of administration; thedesired time course of treatment; the species of mammal; its size, age,and general health; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the kind of concurrenttreatment (i.e., the interaction of the compound of the invention withother co-administered therapeutics); and other relevant circumstances.

Treatment can be initiated with smaller dosages, which are less than theoptimum dose of the compound. Thereafter, the dosage may be increased bysmall increments until the optimum effect under the circumstances isreached. For convenience, the total daily dosage may be divided andadministered in portions during the day if desired. A therapeuticallyeffective anti-proliferative amount and a prophylactically effectiveanti-proliferative amount of a compound of the invention may be expectedto vary from about 0.01 milligram per kilogram of body weight per day(mg/kg/day) to about 100 mg/kg/day.

A preferred dose of the compound of the invention for the presentinvention is the maximum that a patient can tolerate and not developserious side effects. Illustratively, the compound of the presentinvention is administered at a dose of about 0.01 mg/kg to about 100mg/kg of body weight, about 0.01 mg/kg to about 10 mg/kg of body weightor about 0.1 mg/kg to about 10 mg/kg of body weight. Ranges intermediateto the above-recited values are also intended to be part of theinvention.

The percentages in the tests and examples which follows are, unlessotherwise stated, by weight; parts are by weight. Solvent ratios,dilution ratios and concentrations reported for liquid/liquid solutionsare each based on volume.

A. EXAMPLES Abbreviations and Acronyms

Ac acetylaq. aqueous (solution)br. s broad singlet (NMR)cat. catalyticconc. concentratedd doublet (NMR)DCI direct chemical ionization (MS)dd doublet of doublets (NMR)

DMF N,N-dimethylformamide

DMSO dimethylsulfoxideDMSO-d₆ dimethylsulfoxide-d₆ee enantiomeric excessEI electron impact ionization (MS)equiv. equivalent(s)ESI electro-spray ionization (MS)Et ethylGC-MS gas chromatography-coupled mass spectrometryh hour(s)¹H-NMR proton nuclear magnetic resonance spectrometryHOAc acetic acidHPLC high performance/high pressure liquid chromatographyLC-MS liquid chromatography-coupled mass spectrometrym multiplet (NMR)Me methylmin minute(s)MS mass spectrometrym/z mass-to-charge ratio

NMP N-methylpyrrolidin-2-one

of th. of theory (chemical yield)q quartet (NMR)quin quintet (NMR)R_(f) TLC retention factorRP reverse phase (HPLC)rt room temperatureR_(t) retention time (HPLC)s singlet (NMR)TBAF tetra-n-butylammonium fluoridetBu tert-butylTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographyt triplet (NMR)v/v volume-to-volume ratiow/v weight-to-volume ratiow/w weight-to-weight ratio

LC-MS and GC-MS Methods: Method 1 (LC-MS):

Instrument: Micromass ZQ with HPLC Waters Alliance 2795; column:Phenomenex Synergi 2.5μ MAX-RP 100A Mercury, 20 mm×4 mm; eluent A: 1 Lwater+0.5 mL 50% formic acid, eluent B: 1 L acetonitrile+0.5 mL 50%formic acid; gradient: 0.0 min 90% A→0.1 min 90% A→3.0 min 5% A→4.0 min5% A→4.01 min 90% A; flow rate: 2 mL/min; oven: 50° C.; UV detection:210 nm.

Method 2 (LC-MS):

Instrument: Micromass Quattro Premier with HPLC Waters HPLC Acquity;column: Thermo Hypersil GOLD 1.9μ, 50 mm×1 mm; eluent A: 1 L water+0.5mL 50% formic acid, eluent B: 1 L acetonitrile+0.5 mL 50% formic acid;gradient: 0.0 min 90% A→0.1 min 90% A→1.5 min 10% A→2.2 min 10% A; oven:50° C.; flow rate: 0.33 mL/min; UV detection: 210 nm.

Method 3 (LC-MS):

Instrument: Micromass Quattro Micro with HPLC Agilent 1100 Series;column: Thermo Hypersil GOLD 3μ, 20 mm×4 mm; eluent A: 1 L water+0.5 mL50% formic acid, eluent B: 1 L acetonitrile+0.5 mL 50% formic acid;gradient: 0.0 min 100% A→3.0 min 10% A→4.0 min 10% A→4.01 min 100% A(flow rate 2.5 mL/min)→5.00 min 100% A; oven: 50° C.; flow rate: 2mL/min; UV detection: 210 nm.

Method 4 (LC-MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ, 50 mm×1 mm; eluent A: 1 L water+0.25 mL 99% formic acid,eluent B: 1 L acetonitrile+0.25 mL 99% formic acid; gradient: 0.0 min90% A→1.2 min 5% A→2.0 min 5% A; oven: 50° C.; flow rate: 0.40 mL/min;UV detection: 210-400 nm

Method 5 (GC-MS):

Instrument: Micromass GCT, GC 6890; column: Restek RTX-35, 15 m×200μm×0.33 μm; constant flow with helium: 0.88 mL/min; oven: 70° C.; inlet:250° C.; gradient: 70° C., 30° C./min→310° C. (keep for 3 min).

Method 6 (LC-MS):

Instrument: Waters ZQ with HPLC Agilent 1100 Series; UV DAD; column:Thermo Hypersil GOLD 3μ, 20 mm×4 mm; eluent A: 1 L water+0.5 mL 50%formic acid, eluent B: 1 L acetonitrile+0.5 mL 50% formic acid;gradient: 0.0 min 100% A→3.0 min 10% A→4.0 min 10% A→4.1 min 100% A(flow rate 2.5 mL/min); oven: 55° C.; flow rate: 2 mL/min; UV detection:210 nm.

Starting Materials and Intermediates Example 1A3-Methyl-1H-indazole-5-carbaldehyde

Tetrahydrofuran (600 ml) was cooled down to −78° C. under argonatmosphere. At this temperature, a 1.7 M solution of tert-butyllithiumin n-pentane (200 ml) was added dropwise. After 15 minutes at −78° C., asolution of 22.4 g (106.1 mmol) 5-bromo-3-methyl-1H-indazole in THF (300ml) was added dropwise at such a rate that the temperature of thesolution did not exceed −70° C. The mixture was stirred for 30 minutesbefore N,N-dimethylformamide (24.5 ml) was added dropwise. After 20 min,the cooling bath was removed, and stirring was continued for 1 h beforewater (250 ml) was added carefully. The mixture was extracted severaltimes with ethyl acetate (500 ml). The combined organic layers werewashed with saturated aqueous sodium chloride solution, dried oversodium sulfate, and concentrated under reduced pressure to yield 18.5 gof crude 3-methyl-1H-indazole-5-carbaldehyde, which was used in the nextstep without further purification.

¹H-NMR (DMSO-d₆): δ=13.13 (br. s, 1H), 10.01 (s, 1H), 8.40 (s, 1H), 7.81(d, 1H), 7.58 (d, 1H), 2.56 (s, 3H) ppm.

Example 2A(2E)-2-[(3-Methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile

A mixture of 5.0 g (31.2 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 3.61 g (34.3 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate,2.23 ml (39 mmol) acetic acid and 0.31 ml (3.12 mmol) piperidine in drydichloromethane (250 ml) containing 4 Å molecular sieve was stirredunder reflux for 12 h. Upon cooling, a precipitate was formed which wascollected by filtration and washed with saturated aqueous sodiumbicarbonate solution and water. The solid was dissolved in ethanol, andthe molecular sieve was filtered off. The filtrate was concentratedunder reduced pressure, and the residue was treated with ethyl acetateand saturated aqueous sodium carbonate solution. The organic layer waswashed with water, dried, and concentrated under reduced pressure toafford the title compound (3.5 g, 50% of th.) as a pale yellow solidwhich was used in the next step without further purification.

LC-MS (method 1): R_(t)=1.32 min; MS (ESIpos): m/z=226 (M+H)⁺

1H-NMR (400 MHz, DMSO-d₆): δ=13.18 (br. s, 1H), 8.52 (s, 1H), 8.49 (s,1H), 8.19 (d, 1H), 7.69 (d, 1H), 2.55 (br. m, 6H) ppm.

Example 3A 6-Fluoro-3-methyl-1H-indazole-5-carbaldehyde

A solution of 30 g (131 mmol) 5-bromo-6-fluoro-3-methyl-1H-indazole[preparation described in WO 2005/085227-A1, Example 104c); alsocommercially available, CAS Reg.-No. 864773-66-0] in THF (525 ml) wascooled to −45° C. A solution of methylmagnesium chloride in THF (3 M;50.2 ml, 151 mmol) was added dropwise at −45° C., and the resultingsolution was stirred for 40 min at this temperature. Using a dosingpump, 253 ml (354 mmol) of 2-butyllithium solution (1.4 M incyclohexane) were added so that the temperature did not exceed −40° C.The resulting mixture was stirred for 30 min at −40° C., and then 30.2ml (393 mmol) N,N-dimethylformamide were added dropwise keeping thetemperature at −40° C. The resulting mixture was stirred for 30 min at−40° C., then allowed to warm up to room temperature, and slowly pouredinto a volume of 2.8 L of 2 N hydrochloric acid cooled to 5° C.(ice-water bath). The mixture was extracted several times with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane and purified by chromatographyon silica gel (eluent: pentane/ethyl acetate 6:4 v/v) to afford 19.6 g(78% of th.) of the title compound as a pale yellow solid.

MS (ESIpos): m/z=179 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=13.14 (s, 1H), 10.17 (s, 1H), 8.33 (d, 1H),7.37 (d, 1H), 2.54 (s, 3H) ppm.

Example 4A(2E)-2-[(6-Fluoro-3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile

Following the procedure described for Example 2A, the title compound wasprepared using 2.74 g (15.5 mmol)6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 2.6 g(24.8 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate to yield 1.6 g (42% ofth.) of the crude product which was used in the next step withoutfurther purification.

LC-MS (method 4): R_(t)=0.83 min; MS (ESIpos): m/z=244 (M+H)⁺.

Example 5A(2E)-3-(6-Fluoro-3-methyl-1H-indazol-5-yl)-2-[(4-fluorophenyl)carbonyl]prop-2-enenitrile

Following the procedure described for Example 2A, the title compound wasprepared using 500 mg (2.81 mmol)6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 504 mg(3.09 mmol) 3-(4-fluorophenyl)-3-oxopropanenitrile to yield 768 mg (69%of th.) of the crude product (81% purity) which was used in the nextstep without further purification.

LC-MS (method 6): R_(t)=2.24 min; MS (ESIpos): m/z=324 (M+H)⁺.

Example 6A(2E)-2-[(4-Chlorophenyl)carbonyl]-3-(6-fluoro-3-methyl-1H-indazol-5-yl)prop-2-enenitrile

Following the procedure described for Example 2A, the title compound wasprepared using 500 mg (2.81 mmol)6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 566 mg(3.09 mmol) 3-(4-chlorophenyl)-3-oxopropanenitrile to yield 830 mg (66%of th.) of the crude product (76% purity) which was used in the nextstep without further purification.

LC-MS (method 6): R_(t)=2.39 min; MS (ESIpos): m/z=340 (M+H)⁺.

Example 7A 3-Amino-3-[6-(trifluoromethyl)pyridin-2-yl]prop-2-enenitrile

A solution of 2.08 ml (13.07 mmol) diisopropylamine in dry THF (12 ml)was cooled to −70° C. under inert gas atmosphere, and 9.26 ml (14.8mmol) n-butyllithium solution (1.6 M in hexanes) were added dropwise.Then, a solution of 688 μl (13.07 mmol) acetonitrile in dry THF (10 ml)was slowly added over 10 min. The resulting solution was stirred forfurther 30 min at −70° C. before a solution of 1.50 g (8.72 mmol)6-(trifluoromethyl)pyridine-2-carbonitrile in dry THF (10 ml) was added.The mixture was allowed to warm to room temperature and stirred for 12 hbefore water (200 ml) was added slowly. The mixture was extractedseveral times with dichloromethane (100 ml). The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressureto yield 1.2 g (57% of th.) of the crude title compound (89% purity)which was used in the next step without further purification.

LC-MS (method 4): R_(t)=0.88 min; MS (EIpos): m/z=214 (M+H)⁺.

Example 8A 4,4,4-Trifluoro-3-oxobutanenitrile

A flame-dried flask was charged with 20 ml (32 mmol) n-butyllithiumsolution (1.6 M in hexanes) in dry THF (100 ml) under inert gasatmosphere and cooled to −78° C. Next, 1.47 ml (28 mmol) acetonitrilewere slowly added, and the resulting mixture was stirred for 1 h at −74°C. Then, 2.28 ml (20 mmol) ethyl trifluoroacetate were slowly added over5 min maintaining the temperature below −69° C. The reaction mixture wasstirred for 2 h at −45° C. and then quenched by addition of hydrochloricacid (2 M, 9.6 ml) while keeping the temperature below −20° C. Theresulting clear solution was allowed to warm to room temperature andthen concentrated under reduced pressure. The residual aqueous slurrywas extracted several times with diethylether (100 ml portions), and thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure to yield 4.25 g (84% of th.) of the crude titlecompound (54% purity) which was used in the next step without furtherpurification.

GC-MS (method 5): R_(t)=1.05 min; MS (EIpos): m/z=137 (M)⁺.

Example 9A 4,4-Difluoro-3-oxobutanenitrile

A flame-dried flask was charged with 3.8 ml (6.1 mmol) n-butyllithiumsolution (1.6 M in hexanes) in dry THF (19 ml) under inert gasatmosphere and cooled to −78° C. Next, 0.28 ml (5.3 mmol) acetonitrilewere slowly added, and the resulting mixture was stirred for 1 h at −70°C. Then, 0.4 ml (3.8 mmol) ethyl difluoroacetate were slowly added over5 min maintaining the temperature below −69° C. The reaction mixture wasstirred for 2 h at −45° C. and then quenched by addition of hydrochloricacid (2 M, 4.8 ml) while keeping the temperature below −20° C. Theresulting clear solution was allowed to warm to room temperature andthen concentrated under reduced pressure. The crude product thusobtained (1.0 g of 46% purity, 99% of th.) was stored at −21° C. andused in the next step without further purification.

GC-MS (method 5): R_(t)=1.49 min; MS (EIpos): m/z=119 (M)⁺.

Preparation Examples Example 12-(4-Chlorophenyl)-6-(difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile

A mixture of 200 mg (0.542 mmol)(2E)-2-(4-chlorobenzoyl)-3-(6-fluoro-3-methyl-1H-indazol-5-yl)prop-2-enenitrile(Example 6A) and 66 mg (0.542 mmol) 3-amino-4,4-difluorobut-2-enenitrile[obtainable by Thorpe reaction of acetonitrile with2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1(1984)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Then,acetic acid (1.5 ml) was added, and stirring at reflux was continued for6 h. Upon cooling, the mixture was concentrated under reduced pressure,and the residue was directly purified by preparative RP-HPLC(methanol/water+0.1% TFA gradient, final mixture 80:20 v/v) to yield 33mg (14% of th.) of the racemic title compound.

LC-MS (method 2): R_(t)=1.14 min; MS (ESIpos): m/z=440 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.86 (br. s, 1H), 10.46 (s, 1H), 7.79 (d,1H), 7.63-7.55 (m, 4H), 7.38 (d, 1H), 6.79 (t, 1H, ²J_(H,F)=51.8 Hz),5.09 (s, 1H), 2.54 (s, 3H) ppm.

Example 22-(Difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-6-(4-fluorophenyl)-1,4-dihydropyridine-3,5-dicarbonitrile

A mixture of 200 mg (0.569 mmol)(2E)-2-(4-fluorobenzoyl)-3-(6-fluoro-3-methyl-1H-indazol-5-yl)-prop-2-enenitrile(Example 5A) and 69 mg (0.569 mmol) 3-amino-4,4-difluorobut-2-enenitrile[obtainable by Thorpe reaction of acetonitrile with2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1(1984)] in 2-propanol (1 ml) was stirred at reflux for 12 h. Then,acetic acid (1.5 ml) was added, and stirring at reflux was continued for6 h. Upon cooling, the mixture was concentrated under reduced pressure,and the residue was directly purified by preparative RP-HPLC(methanol/water+0.1% TFA gradient, final mixture 80:20 v/v) to yield 36mg (15% of th.) of the racemic title compound.

LC-MS (method 4): R_(t)=0.97 min; MS (ESIpos): m/z=424 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.87 (br. s, 1H), 10.44 (s, 1H), 7.78 (d,1H), 7.61 (m, 2H), 7.41-7.35 (m, 3H), 6.79 (t, 1H, ²J_(H,F)=51.8 Hz),5.08 (s, 1H), 2.54 (s, 3H) ppm.

Example 34-(3-Methyl-1H-indazol-5-yl)-6,6′-bis(trifluoromethyl)-1,4-dihydro-2,2′-bipyridine-3,5-dicarbonitrile

A solution of 150 mg (0.936 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A) in n-pentanol (4 ml) containing powdered 4 Å molecularsieve was treated with 128 mg (0.936 mmol)4,4,4-trifluoro-3-oxobutanenitrile (Example 8A) and stirred at 130° C.for 1 h. Then, 94 mg (0.44 mmol)3-amino-3-[6-(trifluoromethyl)pyridin-2-yl]prop-2-enenitrile (Example7A) and acetic acid (1.2 ml) were added, and the mixture was stirred at130° C. for further 15 min. Upon cooling, water (6 ml) was added, themixture was filtered, and the filtrate was concentrated under reducedpressure. The residue was dissolved in ethyl acetate (30 ml), and thesolution was washed several times with brine, then with water, driedover sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in THF (1 ml) containing 4 Å molecular sieve. Asolution of tetra-n-butylammonium fluoride (TBAF, 1 N in THF, 1.5 ml)was added, and the mixture was stirred at 70° C. for 5 h. Upon cooling,the mixture was concentrated under reduced pressure, and the crudeproduct was finally purified by preparative RP-HPLC (methanol/water+0.1%TFA gradient) to yield 15 mg (7% of th.) of the racemic title compound.

LC-MS (method 2): R_(t)=1.23 min; MS (ESIpos): m/z=475 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.80 (br. s, 1H), 10.70 (s, 1H), 8.32 (t,1H), 8.10 (m, 2H), 7.74 (s, 1H), 7.61 (d, 1H), 7.44 (dd, 1H), 5.03 (s,1H), 2.50 (s, 3H) ppm.

Example 42-(Difluoromethyl)-4-(3-methyl-1H-indazol-5-yl)-6-phenyl-1,4-dihydropyridine-3,5-dicarbonitrile

A mixture of 200 mg (1.25 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 217 mg (1.50 mmol) 3-oxo-3-phenylpropanenitrile and 147 mg(1.25 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpereaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React.15, 1 (1967), ibid. 31, 1 (1984)] in 1-pentanol (1.2 ml) containingpowdered 4 Å molecular sieve was heated to 105° C. overnight. Aftercooling, the reaction mixture was diluted with acetonitrile and directlypurified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient)followed by chromatography on silica gel (eluent:toluene/dichloromethane/methanol 10:5:1 v/v) to afford 93 mg (19% ofth.) of the racemic title compound.

LC-MS (method 4): R_(t)=0.93 min; MS (ESIpos): m/z=388 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.78 (s, 1H), 10.38 (s, 1H), 7.68 (s, 1H),7.60-7.49 (m, 6H), 7.40 (d, 1H), 6.78 (t, 1H, ²J_(H,F)=52 Hz), 4.83 (s,1H), 2.48 (s, 3H) ppm.

The following compounds were prepared in analogy to the proceduredescribed in Example 4; purification was carried out by preparativeRP-HPLC using a methanol/water+0.1% TFA gradient followed bychromatography on silica gel (eluent: toluene/dichloromethane/methanol10:10:1 v/v):

Name/Structure Example (yield) Analytical data 5

LC-MS (method 4): R_(t) = 1.01 min; m/z = 422 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.78 (s, 1H), 10.41 (s, 1H), 7.68 (s, 1H), 7.65-7.56 (m,5H), 7.40 (d, 1H), 6.79 (t, 1H, ²J_(H,F) = 52 Hz), 4.86 (s, 1H), 2.49(s, 3H) ppm. 6

LC-MS (method 4): R_(t) = 0.94 min; m/z = 406 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.76 (s, 1H), 10.38 (s, 1H), 7.69-7.56 (m, 4H), 7.43-7.34(m, 3H), 6.79 (t, 1H, ²J_(H,F) = 52 Hz), 4.85 (s, 1H), 2.49 (s, 3H) ppm.7

LC-MS (method 4): R_(t) = 0.96 min; m/z = 424 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.79 (s, 1H), 10.43 (s, 1H), 7.69 (s, 1H), 7.58 (d, 1H),7.56-7.36 (m, 4H), 6.79 (t, 1H, ²J_(H,F) = 52 Hz), 4.88 (s, 1H), 2.49(s, 3H) ppm. 8

LC-MS (method 4): R_(t) = 0.96 min; m/z = 418 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.76 (s, 1H), 10.28 (s, 1H), 7.64 (s, 1H), 7.58 (d, 1H),7.50 (d, 2H), 7.39 (d, 1H), 7.08 (d, 2H), 6.78 (t, 1H, ²J_(H,F) = 52Hz), 4.80 (s, 1H), 3.81 (s, 3H), 2.49 (s, 3H) ppm. ¹silica gelchromatography was carried out using toluene/dichloromethane/methanol10:10:0.5 v/v as eluent; ²initial purification by preparative RP-HPLCusing a methanol/water + 0.1% TFA gradient, followed by furtherpurification first by chromatography on silica gel (eluent:toluene/dichloromethane/methanol 10:10:0.5 v/v) and second bypreparative RP-HPLC [column: Sunfire C18 OBD, 5 μm, 19 mm × 150 mm;eluent: water/methanol 60:40 → 0:100 v/v gradient; flow rate: 25 ml/min;temperature: 40° C.; UV detection: 254 nm].

Example 9 and Example 102-(Difluoromethyl)-6-(4-fluorophenyl)-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile(Enantiomer 1 and 2)

The racemic compound from Example 6 (60 mg) was separated into theenantiomers by HPLC chromatography on a chiral phase [column: DaicelChiralpak AD-H, 5 μm, 250 mm×20 mm; eluent: iso-hexane/ethanol 80:20v/v; flow rate: 15 ml/min; temperature: 30° C.; UV detection: 220 nm]:

Example 9 Enantiomer 1

Yield: 25 mg (>99% ee)

R_(t)=4.88 min [column: Daicel Chiralcel AD-H, 5 μm, 250 mm×4.6 mm;eluent: iso-hexane/ethanol 80:20+0.2% diethylamine; flow rate: 1 ml/min;temperature: 30° C.; UV detection: 235 nm].

Example 10 Enantiomer

Yield: 26 mg (>99% ee)

R_(t)=6.03 min [column: Daicel Chiralcel AD-H, 5 pin, 250 mm×4.6 mm;eluent: iso-hexane/ethanol 80:20+0.2% diethylamine; flow rate: 1 ml/min;temperature: 30° C.; UV detection: 235 nm].

Example 114-(3-Methyl-1H-indazol-5-yl)-2-phenyl-6-trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile

A mixture of 300 mg (1.87 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 272 mg (1.87 mmol) 3-oxo-3-phenylpropanenitrile and 1019mg (7.49 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A.W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42(1969)] in 1-pentanol (1.9 ml) containing powdered 4 Å molecular sievewas heated to 105° C. overnight. After cooling, the reaction mixture wasdiluted with acetonitrile and directly purified by preparative RP-HPLC(acetonitrile/water+0.1% TFA gradient) to afford 285 mg (37% of th.) ofthe racemic title compound.

LC-MS (method 4): R_(t)=0.99 min; MS (ESIpos): m/z=406 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.80 (br. s, 1H), 10.68 (s, 1H), 7.70 (s,1H), 7.62-7.50 (m, 6H), 7.42 (d, 1H), 4.92 (s, 1H), 2.54 (s, 3H) ppm.

The following compounds were prepared in analogy to the proceduredescribed in Example 11; purification was carried out by preparativeRP-HPLC using a methanol/water+0.1% TFA gradient followed bychromatography on silica gel (eluent: toluene/dichloromethane/methanol10:10:1 v/v):

Name/Structure Example (yield) Analytical data 12

LC-MS (method 4): R_(t) = 1.03 min; m/z = 440 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.80 (s, 1H), 10.68 (s, 1H), 7.71 (s, 1H), 7.66-7.57 (m,5H), 7.42 (d, 1H), 4.94 (s, 1H), 2.54 (s, 3H) ppm. 13

LC-MS (method 2): R_(t) = 1.12 min; m/z = 424 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.80 (s, 1H), 10.68 (s, 1H), 7.70 (s, 1H), 7.68-7.57 (m,3H), 7.48-7.36 (m, 3H), 4.93 (s, 1H), 2.54 (s, 3H) ppm. 14

LC-MS (method 4): R_(t) = 0.99 min; m/z = 442 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.80 (br. s, 1H), 10.82 (s, 1H), 7.71- 7.67 (m, 2H), 7.61(d, 1H), 7.51 (m, 1H), 7.43 (d, 1H), 7.29 (m, 1H), 4.99 (s, 1H), 2.54(s, 3H) ppm. 15

LC-MS (method 3): R_(t) = 2.13 min; m/z = 436 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.78 (s, 1H), 10.59 (s, 1H), 7.68 (s, 1H), 7.59 (d, 1H),7.51 (d, 2H), 7.39 (d, 1H), 7.08 (d, 2H), 4.88 (s, 1H), 3.81 (s, 3H),2.54 (s, 3H) ppm. 16

LC-MS (method 4): R_(t) = 1.00 min; m/z = 424 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.79 (s, 1H), 10.70 (s, 1H), 7.71 (s, 1H), 7.62-7.55 (m,2H), 7.52-7.38 (m, 4H), 4.96 (s, 1H), 2.54 (s, 3H) ppm. 17

LC-MS (method 3): R_(t) = 2.17 min; m/z = 442 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.80 (br. s, 1H), 10.70 (s, 1H), 7.72 (s, 1H), 7.59 (d,1H), 7.54-7.38 (m, 4H), 4.96 (s, 1H), 2.54 (s, 3H) ppm. 18

LC-MS (method 3): R_(t) = 2.31 min; m/z = 474 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.80 (s, 1H), 10.73 (s, 1H), 7.92 (d, 2H), 7.81 (d, 2H),7.72 (s, 1H), 7.60 (d, 1H), 7.47 (d, 1H), 4.99 (s, 1H), 2.54 (s, 3H)ppm. 19

LC-MS (method 4): R_(t) = 1.04 min; m/z = 458 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.80 (s, 1H), 10.65 (s, 1H), 7.90 (dd, 1H), 7.72 (s, 1H),7.68-7.55 (m, 3H), 7.48 (d, 1H), 4.97 (s, 1H), 2.54 (s, 3H) ppm. 20

LC-MS (method 4): R_(t) = 0.90 min; m/z = 441 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.80 (br. s, 1H), 10.92 (s, 1H), 8.62- 8.58 (m, 1H),8.20-8.09 (m, 1H), 7.78 (s, 1H), 7.68-7.56 (m, 2H), 7.53-7.46 (m, 1H),5.10-4.98 (m, 1H), 2.54 (s, 3H) ppm. 21

LC-MS (method 3): R_(t) = 1.85 min; m/z = 411 (M + H)⁺ ¹H-NMR (400 MHz,DMSO-d₆): δ = 12.79 (s, 1H), 10.81 (s, 1H), 8.59 (s, 1H), 7.69 (s, 1H),7.59 (d, 1H), 7.36 (d, 1H), 4.99 (s, 1H), 2.54 (s, 3H), 2.15 (s, 3H)ppm. ¹without further purification by silica gel chromatography; ²thereaction was performed in a microwave oven at 150° C. (30 min);purification was carried out by preparative RP-HPLC using amethanol/water + 0.1% TFA gradient followed by chromatography on silicagel (eluent: toluene/dichloromethane/ methanol 5:5:1 v/v).

Example 22 and Example 232-(4-Fluorophenyl)-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile(Enantiomer 1 and 2)

The racemic compound from Example 13 (200 mg) was separated into theenantiomers by HPLC chromatography on a chiral phase [column: DaicelChiralpak AD-H, 5 μm, 250 mm×20 mm; eluent: iso-hexane/ethanol 85:15v/v; flow rate: 15 ml/min; temperature: 30° C.; UV detection: 220 nm]:

Example 22 Enantiomer 1

Yield: 87 mg (>99% ee)

R_(t)=4.01 min [column: Daicel Chiralcel AD-H, 5 pin, 250 mm×4.6 mm;eluent: iso-hexane/ethanol 80:20+0.2% diethylamine; flow rate: 1 ml/min;temperature: 30° C.; UV detection: 235 nm].

Example 23 Enantiomer 2

Yield: 92 mg (>99% ee)

R_(t)=4.45 min [column: Daicel Chiralcel AD-H, 5 pin, 250 mm×4.6 mm;eluent: iso-hexane/ethanol 80:20+0.2% diethylamine; flow rate: 1 ml/min;temperature: 30° C.; UV detection: 235 nm].

Examples A and B described below are close structural analogs of thecompounds of the present invention featuring a non-fluoro-substituted(i.e. unsubstituted) methyl group in 6-position of the1,4-dihydropyridine ring. c-Met kinase inhibiting compounds of this typehave previously been described in WO 2008/071451-A1. In the context ofthe present invention, the compounds specified in Examples A and B werechosen from the generic disclosure of WO 2008/071451-A1 for comparativeinvestigation of structure-activity and structure-permeabilityrelationships (see biological section below). The preparation of thesecompounds was accomplished by adaptation of the procedures describedabove.

Comparative Example A2-(4-Methoxyphenyl)-6-methyl-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile

A mixture of 250 mg (1.56 mmol) 3-methyl-1H-indazole-5-carbaldehyde(Example 1A), 328 mg (1.88 mmol) 3-(4-methoxyphenyl)-3-oxopropanenitrileand 128 mg (1.56 mmol) 3-aminobut-2-enenitrile in 1-pentanol (1.55 ml)containing powdered 4 Å molecular sieve was heated to 105° C. overnight.After cooling, the reaction mixture was diluted with acetonitrile anddirectly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFAgradient) to afford 180 mg (30% of th.) of the racemic title compound.

LC-MS (method 4): R_(t)=0.91 min; MS (ESIpos): m/z=382 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.70 (br. s, 1H), 9.64 (s, 1H), 7.60 (s,1H), 7.57-7.48 (m, 3H), 7.38 (d, 1H), 7.08 (d, 2H), 4.62 (s, 1H), 3.80(s, 3H), 2.48 (s, 3H), 2.11 (s, 3H) ppm.

Comparative Example B2-(4-Fluorophenyl)-6-methyl-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile

A mixture of 200 mg (0.89 mmol)(2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutane-nitrile(Example 2A), 159 mg (0.98 mmol) 3-(4-fluorophenyl)-3-oxopropanenitrileand 205 mg (2.66 mmol) ammonium acetate in ethanol/acetic acid (4:1 v/v,11 ml) was heated to reflux overnight. After cooling, the reactionmixture was directly purified by preparative RP-HPLC(acetonitrile/water+0.1% TFA gradient) to afford 136 mg (41% of th.) ofthe racemic title compound.

LC-MS (method 2): R_(t)=1.04 min; MS (ESIpos): m/z=370 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=12.70 (br. s, 1H), 9.74 (s, 1H), 7.64-7.59(m, 3H), 7.53 (d, 1H), 7.40-7.33 (m, 3H), 4.68 (s, 1H), 2.48 (s, 3H),2.11 (s, 3H) ppm.

B. EVALUATION OF BIOLOGICAL ACTIVITY

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused:

c-Met Receptor Tyrosine Kinase Activity Assay (NADH Read-Out):

Recombinant human c-Met protein (Invitrogen, Carlsbad, Calif., USA) isused. As substrate for the kinase reaction the peptide KKKSPGEYVNIEFG(JPT, Germany) is used. For the assay, 1 μL of a 51-fold concentratedsolution of the test compound in DMSO is pipetted into a white 384-wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany). 25 μL of asolution of c-Met (final concentration 30 nM) and pyruvatekinase/lactate dehydrogenase (Roche Diagnostics, Mannheim, Germany;final concentration 8 mg/L) in assay buffer[3-(N-morpholino)propanesulfonic acid (MOPS), 50 mM, pH 7; MgCl₂, 10 mM;bovine serum albumin (BSA), 0.01%; Triton X 100, 0.01%; DTT, 2 mM] areadded, and the mixture is incubated for 5 min at room temperature. Then,the kinase reaction is started by the addition of 25 μL of a solution ofadenosine triphosphate (ATP, final concentration 30 μM), substrate(final concentration 100 μM), nicotinamide adenine dinucleotide (NADH,final concentration 50 μM) and dithiothreitol (DTT, final concentration2 mM) in assay buffer, and the resulting mixture is incubated for areaction time of 100 min at 32° C.

Subsequently, the amount of phosphorylated substrate is evaluated bymeasurement of the decrease of NADH fluorescence. Therefore, thefluorescence emissions at 465 nm after excitation at 340 nm is measuredin a fluorescence reader, e.g. Tecan Ultra (Tecan, Männedorf,Switzerland). The data are normalised (enzyme reaction withoutinhibitor=0% inhibition; all other assay components but no enzyme=100%inhibition). Normally, test compounds are tested on the same microtiterplate at 9 different concentrations in the range of 10 μM to 1 nM (10μM, 3.1 μM, 1.0 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001μM; dilution series prepared before the assay at the level of the51-fold concentrated stock solutions by serial 1:3 dilutions) induplicate for each concentration, and IC₅₀ values are calculated usingan inhouse software.

Some representative IC₅₀ values are listed in Table 1 below togetherwith corresponding data for two structural analogs having anunsubstituted methyl group in 6-position of the 1,4-dihydropyridine ring(comparative Examples A and B, see experimental section above; disclosedgenerically in WO 2008/071451-A1):

TABLE 1 Example No. IC₅₀ [μM]  4 0.023  6 0.021  8 0.018 10 0.013 130.028 20 0.031 A 0.025 B 0.015c-Met Receptor Tyrosine Kinase Homogeneous Time-Resolved FluorescenceAssay (Alternative Format):

The N-terminally His6-tagged recombinant kinase domain of the humanc-Met (amino acids 960-1390), expressed in insect cells (SF21) andpurified by Ni-NTA affinity chromatography and consecutive sizeexclusion chromatography (Superdex 200), is used. Alternatively,commercially available c-Met (Millipore) can be used. As substrate forthe kinase reaction, the biotinylated poly-Glu,Tyr (4:1) copolymer(#61GT0BLC, Cis Biointernational, Marcoule, France) is used.

For the assay, 50 nL of a 100-fold concentrated solution of the testcompound in DMSO is pipetted into a black low-volume 384-well microtiterplate (Greiner Bio-One, Frickenhausen, Germany). 2 μl, of a solution ofc-Met in assay buffer [25 mM Hepes/NaOH, pH 7.5; 5 mM MgCl₂; 5 mM MnCl₂;2 mM dithiothreitol; 0.1% (v/v) Tween 20 (Sigma); 0.1% (w/v) bovineserum albumin] are added, and the mixture is incubated for 15 min at 22°C. to allow pre-binding of the test compound to the enzyme before thestart of the kinase reaction. Then, the kinase reaction is started bythe addition of 3 μl, of a solution of adenosine triphosphate (ATP, 16.7μM; final concentration in the 5 μl, assay volume is 10 μM) andsubstrate (2.27 μg/mL, final concentration in the 5 μl, assay volume is1.36 μg/mL˜30 nM) in assay buffer, and the resulting mixture isincubated for a reaction time of 30 min at 22° C. The concentration ofc-Met in the assay is adjusted depending on the activity of the enzymelot and is appropriately chosen to have the assay in the linear range;typical enzyme concentrations are in the range of about 0.03 nM (finalconcentration in the 5 μl, assay volume). The reaction is stopped by theaddition of 5 μL of a solution of HTRF detection reagents [40 nMstreptavidine-XLent and 2.4 nM PT66-Eu-chelate, an europium-chelatelabelled anti-phosphotyrosine antibody (Perkin-Elmer)] in an aqueousEDTA solution [100 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mMHEPES/NaOH, pH 7.5].

The resulting mixture is incubated for 1 h at 22° C. to allow thebinding of the biotinylated phosphorylated peptide to thestreptavidine-XLent and the PT66-Eu-chelate. Subsequently, the amount ofphosphorylated substrate is evaluated by measurement of the resonanceenergy transfer from the PT66-Eu-chelate to the streptavidine-XLent.Therefore, the fluorescence emissions at 620 nm and 665 nm afterexcitation at 350 nm are measured in an HTRF reader, e.g. Rubystar (BMGLabtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). Theratio of the emissions at 665 nm and at 622 nm is taken as the measurefor the amount of phosphorylated substrate. The data are normalised(enzyme reaction without inhibitor=0% inhibition; all other assaycomponents but no enzyme=100% inhibition). Normally, test compounds aretested on the same microtiter plate at 10 different concentrations inthe range of 20 μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82nM, 27 nM, 9.2 nM, 3.1 nM and 1 nM; dilution series prepared before theassay at the level of the 100-fold concentrated stock solutions byserial 1:3 dilutions) in duplicate for each concentration, and IC₅₀values are calculated by a 4-parameter-fit using an inhouse software.

Phospho-c-Met Assay:

This is a cell based, ELISA-like assay [Meso Scale Discovery (MSD),Gaithersburg, Md., USA] using MKN-45 tumor cells (gastric carcinoma,purchased from ATCC) without growth factor stimulation. The cells areplated in full growth media (10 000 cells/well) in 96-well plates on dayone. On day two, after a two-hour drug treatment in serum-free media,cells are washed and then lysed (60 μl/well using MSD recommended lysisbuffer) and frozen at −80° C. Also on day two, non-specificantibody-binding sites on the MSD phospho-Met plates are blocked withMSD Blocking Solution A overnight at 4° C. On day three, frozen lysatesare thawed on ice, and 25 μl of lysate is transferred to the MSDphospho-Met plate, for 1 hour with shaking, after washing once withTris-buffered saline+0.05% Tween 20 (TBST). After removing the unboundproteins, the Sulfa-TAG anti-Met antibody from MSD is added at a finalconcentration of 5 nM in antibody dilution buffer (following protocol ofMSD) to the plate for 1 hour with shaking. The plate is then washed withTBST buffer three times before adding 1×MSD Read Buffer. The plate isthen read on the MSD Discovery Workstation instrument. Raw data,including wells with 10 μM of a reference compound (minimum signal), andDMSO wells without any drug treatment (maximum signal), are entered intothe Analyze 5 program for IC₅₀ value determinations.

Cellular Phospho-c-Met Assay:

Human gastric adenocarcinoma cells (MKN45, purchased from ATCC) seededon 384-well microtiter plates (9000 cells/well) are incubated in 25 μlfull growth media for 24 h at 37° C. with 5% CO₂. On day two, after atwo-hour drug treatment in serum-reduced media containing 0.1% FCS,cells are washed and lysed. Lysates are transferred to BSA-blockedplates with prebound c-Met capture antibody [purchased from MesoscaleDiscovery (MSD), Gaithersburg, Md., USA] for 1 hour with shaking, afterwashing once with Tris-buffered saline+0.05% Tween 20 (TBST). Followingthe MSD protocol, the Sulfa-TAG anti-phospho-c-Met detection antibody isadded at a final concentration of 5 nM in antibody dilution buffer tothe plate for 1 hour with shaking at RT. After washing the wells withTris buffer, 1× reading buffer is added, and the plates are measured onthe Sector Imager 6000 (purchased from Mesoscale). IC₅₀ values arecalculated from dose-response curves using Marquardt-Levenberg-Fit.

In-Vitro Tumor Cell Proliferation Assay

The adherent tumor cell proliferation assay used to test the compoundsof the present invention involves a read-out called Cell Titre-Glodeveloped by Promega [B. A. Cunningham, “A Growing Issue: CellProliferation Assays. Modern kits ease quantification of cell growth”,The Scientist 2001, 15 (13), 26; S. P. Crouch et al., “The use of ATPbioluminescence as a measure of cell proliferation and cytotoxicity”,Journal of Immunological Methods 1993, 160, 81-88]. Generation of aluminescent signal corresponds to the amount of ATP present, which isdirectly proportional to the number of metabolically active(proliferating) cells.

H460 cells (lung carcinoma, purchased from ATCC) are plated in 96-wellplates at 3000 cells/well in complete media with 10% fetal calf serumand incubated 24 hours at 37° C. Twenty-four hours after plating, testcompounds are added over a final concentration range of 10 nM to 20 μMin serial dilutions at a final DMSO concentration of 0.2%. Cells areincubated for 72 hours at 37° C. in complete growth media after additionof the test compound. On day 4, using a Promega Cell Titre-GloLuminescent® assay kit, the cells are lysed, and 100 μl ofsubstrate/buffer mixture is added to each well, mixed and incubated atroom temperature for 8 minutes. The samples are read on a luminometer tomeasure the amount of ATP present in the cell lysates from each well,which corresponds to the number of viable cells in that well. Valuesread at 24-hour incubation are subtracted as Day 0. For determination ofIC₅₀ values, a linear regression analysis can be used to determine thedrug concentration which results in a 50% inhibition of cellproliferation using this assay format. This protocol can be applied todifferent cell lines of interest, which include, but not limited to,CAKI-1, MNK-45, GTL-16, HCC2998, K562, H441, K812, MEG01, SUP15 andHCT116.

Caco-2 Permeability Assay:

The in vitro permeation of a test compound across a Caco-2 cellmonolayer is a well-established assay system to predict the permeabilityfrom the gastro-intestinal tract [cf. P. Artursson and J. Karlsson:Correlation between oral drug absorption in humans and apparent drugpermeability coefficients in human intestinal epithelial (Caco-2) cells,Biochem. Biophys. 175 (3), 880-885 (1991)]. The permeability of thecompounds of the present invention in such Caco-2 cells was determinedas described below:

Human Caco-2 cells (ACC No. 169, DSMZ, German Collection ofMicroorganisms and Cell Cultures, Braunschweig, Germany) are seeded on24-well insert plates and are allowed to grow for 14-16 days. Forpermeability studies, the test compounds are dissolved in DMSO anddiluted to the final test concentration of 2 μM with transport buffer[Hanks' Buffered Salt Solution, Gibco/Invitrogen, further supplementedwith glucose (final concentration 19.9 mM) and HEPES (finalconcentration 9.8 mM)]. For determination of the apical to basolateralpermeability (P_(app)A-B), the test compound solution is added to theapical side of the cell monolayer and transport buffer to thebasolateral side of the monolayer; for determination of the basolateralto apical permeability (P_(app)B-A), the test compound solution is addedto the basolateral side of the cell monolayer and transport buffer tothe apical side of the monolayer. Samples are taken from the donorcompartment at the beginning of the experiment to confirm mass balance.After an incubation of 2 h at 37° C., samples are taken from bothcompartments. Samples are analyzed by LC-MS/MS, and the apparentpermeability coefficients are calculated. Lucifer Yellow permeability isassayed for each cell monolayer to ensure cell monolayer integrity, andthe permeability of Atenolol (low permeability marker) and Sulfasalazine(marker for active excretion) is determined for each batch as qualitycontrol.

Representative results from this assay are listed in Table 2 belowtogether with corresponding data for two structural analogs having anunsubstituted methyl group in 6-position of the 1,4-dihydropyridine ring(comparative Examples A and B, see experimental section above; disclosedgenerically in WO 2008/071451-A1):

TABLE 2 Caco-2 permeability Example No. P_(app)A-B [nm/s] 6 150 8 17013  158 A 99 B 62

Although the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations of theinvention may be devised by others skilled in the art without departingfrom the true spirit and scope of the invention. The claims are intendedto be construed to include all such embodiments and equivalentvariations.

C. EXAMPLES RELATING TO PHARMACEUTICAL COMPOSITIONS

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile i.v. Solution:

A 5 mg/ml solution of the desired compound of this invention can be madeusing sterile, injectable water, and the pH is adjusted if necessary.The solution is diluted for administration to 1-2 mg/ml with sterile 5%dextrose and is administered as an i.v. infusion over about 60 minutes.

Lyophilized Powder for i.v. Administration:

A sterile preparation can be prepared with (i) 100-1000 mg of thedesired compound of this invention as a lyophilized powder, (ii) 32-327mg/ml sodium citrate, and (iii) 300-3000 mg Dextran 40. The formulationis reconstituted with sterile, injectable saline or 5% dextrose to aconcentration of 10 to 20 mg/ml, which is further diluted with saline or5% dextrose to 0.2 to 0.4 mg/ml, and is administered either as i.v.bolus or by i.v. infusion over 15-60 minutes.

Intramuscular Suspension:

The following solution or suspension can be prepared for intramuscularinjection:

50 mg/ml of the desired, water-insoluble compound of this invention; 5mg/ml sodium carboxymethylcellulose; 4 mg/mL TWEEN 80; 9 mg/ml sodiumchloride; 9 mg/ml benzyl alcohol.

Hard Shell Capsules:

A large number of unit capsules are prepared by filling standardtwo-piece hard galantine capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesiumstearate.

Soft Gelatin Capsules:

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into molten gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules arewashed and dried. The active ingredient can be dissolved in a mixture ofpolyethylene glycol, glycerin and sorbitol to prepare a water-misciblemedicine mix.

Tablets:

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate aqueousand non-aqueous coatings may be applied to increase palatability,improve elegance and stability, or delay absorption.

1. A compound of formula (I)

wherein Ar is phenyl or 5- or 6-membered heteroaryl each of which may besubstituted with one or two substituents independently selected from thegroup consisting of fluoro, chloro, bromo, cyano, nitro, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, amino and mono-(C₁-C₄)-alkylamino, wherein said(C₁-C₄)-alkyl and (C₁-C₄)-alkoxy substituents may be further substitutedwith up to three fluoro atoms, R¹ is hydrogen or fluoro, R² is hydrogenor methyl, R³ is hydrogen or fluoro, and R⁴ is hydrogen or(C₁-C₄)-alkyl, or a pharmaceutically acceptable salt, hydrate and/orsolvate thereof.
 2. The compound of formula (I) according to claim 1,wherein Ar is phenyl, pyridyl, pyrimidinyl, thienyl, pyrazolyl,imidazolyl, oxazolyl, thiazolyl, isoxazolyl or isothiazolyl each ofwhich may be substituted with one or two substituents independentlyselected from the group consisting of fluoro, chloro, cyano, methyl,difluoromethyl, trifluoromethyl, ethyl, methoxy, trifluoromethoxy andethoxy, R¹ is hydrogen or fluoro, R² is hydrogen, R³ is hydrogen orfluoro, and R⁴ is hydrogen, methyl or ethyl, or a pharmaceuticallyacceptable salt, hydrate and/or solvate thereof.
 3. The compound offormula (I) according to claim 1, wherein Ar is phenyl, pyridyl oroxazolyl each of which may be substituted with one or two substituentsindependently selected from the group consisting of fluoro, chloro,methyl, trifluoro-methyl and methoxy, R¹ is hydrogen or fluoro, R² ishydrogen, R³ is hydrogen or fluoro, and R⁴ is methyl, or apharmaceutically acceptable salt, hydrate and/or solvate thereof.
 4. Aprocess for preparing a compound of formula (I) as defined in claim 1,wherein an indazolyl aldehyde of formula (II)

wherein R³ and R⁴ have the meanings indicated in claim 1, is reactedeither [A] with a ketonitrile of formula (III)

wherein Ar has the meaning indicated in claim 1, in the presence of anacid, acid/base combination and/or dehydrating agent to give a compoundof formula (IV)

wherein Ar, R³ and R⁴ have the meanings indicated in claim 1, and thelatter is then condensed with an enaminonitrile of formula (V)

wherein R¹ has the meaning indicated in claim 1, to yield the compoundof formula (I-A)

wherein Ar, R¹, R³ and R⁴ have the meanings indicated in claim 1, or [B]with a ketonitrile of formula (VI)

wherein R¹ has the meaning indicated in claim 1, optionally in thepresence of a base and/or dehydrating agent to give a compound offormula (VII)

wherein R¹, R³ and R⁴ have the meanings indicated in claim 1, and thelatter is then condensed with an enaminonitrile of formula (VIII)

wherein Ar has the meaning indicated in claim 1, in the presence of anacid to also yield the compound of formula (I-A)

wherein Ar, R¹, R³ and R⁴ have the meanings indicated in claim 1,optionally followed by dihydropyridine N-methylation employing acompound of formula (IX)CH₃—X  (IX), wherein X represents a leaving group, in the presence of abase to give the compound of formula (I-B)

wherein Ar, R¹, R³ and R⁴ have the meanings indicated in claim 1, andoptionally followed by (i) separating the compound (I-A) or (I-B) intoits enantiomers and/or diastereomers, and/or (ii) converting thecompound (I-A) or (I-B) into a hydrate or solvate thereof by treatmentwith a corresponding solvent.
 5. (canceled)
 6. (canceled)
 7. (canceled)8. A pharmaceutical composition comprising a compound as defined inclaim 1, or a pharmaceutically acceptable hydrate or solvate thereof,and a pharmaceutically acceptable excipient.
 9. The pharmaceuticalcomposition of claim 8 further comprising one or more additionaltherapeutic agents.
 10. The pharmaceutical composition of claim 9,wherein the additional therapeutic agent is an anti-tumor agent. 11.(canceled)
 12. A method of treating or preventing a cell proliferativedisorder in a mammal, comprising administering to a mammal in needthereof a therapeutically effective amount of a compound as defined inclaim
 1. 13. The method of claim 12, wherein the cell proliferativedisorder is cancer.
 14. The method of claim 13, wherein the cancer is acancer of the breast, respiratory tract, brain, reproductive organs,digestive tract, urinary tract, eye, liver, skin, head or neck, thyroid,parathyroid, or a distant metastasis of a solid tumor.
 15. The method ofclaim 13, wherein the compound as defined in claim 1 is administered inconjunction with surgery or radiation therapy.